Associate Professor
Marieke van der Zalm
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Project Title
The long-term consequences of pulmonary tuberculosis and respiratory viruses on lung health in young South African children
EDCTP Project
TMA2019SFP2836
EDCTP Program
EDCTP2
EDCTP Project Call
Senior Fellowship Plus (SFP)
Project Objectives
The overarching goal of the TB-lung FACT2 project is to improve our current understanding of the long-term impact of PTB and other LRTIs on lung health in children living in resource-limited settings.
Study Design
Prospective observational cohort study
Project Summary
The TB-lung FACT2 project aims to investigate the long-term impact of PTB and common viral LRTIs on lung health in young children across representative and well-characterised disease categories and spectrum in order to reduce respiratory morbidlity and mortality. We propose to use the well-established, previously EDCTP supported and unique TB-lung FACT cohort of 300 well-characterized HIV-infected and uninfected children aged 0-13 years (median age 2 years), systematically investigated for M. tuberculosis and other respiratory pathogens. This cohort is complemented by 100 healthy controls to support the rigorous investigation of the long-term lung health impact of TB and LRTI in children. Through this proposed research, we will extend the current 6 months follow-up of the existing TB-lung FACT cohort for an additional 30 months (36 months total) to measure lung function longitudinally, using state of the-art rigorous lung function testing including oscillometry, plethysmography and diffusion capacity. For analytical purposes, children will be classified into three groups: 1) TB cases, 2) children in whom TB is excluded after investigation (“ill controls”), and 3) age-matched healthy controls. The INHALE study aims to investigate the impact of PTB and viral LRTIs on lung health in young Mozambican children. The study will leverage a cohort of children with presumptive PTB enrolled in the Stool4TB project (EDCTP funded), which aims to recruit HIV infected and uninfected children under 8 years of age by adding lung health assessment, including the sampling for respiratory virus infections and extend follow-up for intermediate lung health outcomes. The project will build capacity for clinical pediatric lung health research in rural Mozambique, within the context of a well-established African research center with an extensive track record for research on TB and infectious diseases (The Centro de Investigação em Saúde de Manhiça / Fundação Manhiça (CISM/ FM).
Host Organisation
| Department | Institution | Country |
|---|---|---|
| Stellenbosch University | South Africa |
Sites
Project Title
The impact of pulmonary tuberculosis and other lower respiratory tract pathogens on lung function in young South African children
EDCTP Project
TMA2015CDF1012
EDCTP Program
EDCTP2
EDCTP Project Call
Career Development Fellowship (CDF)
Project Objectives
To investigate the effect of TB, TB/ HIV co-infection and other common respiratory pathogens on lung function in young children.
Study Design
Prospective observational cohort study of children with suspected pulmonary TB including healthy controls
Project Summary
This EDCTP funded project called TB- lung FACT or Umoya study (“breath” in isiXhosa) is a hospital-based study that rigorously and systematically investigates the lung health of a cohort of 300 HIV-infected and uninfected children 0-13 years of age, with different spectrum of intrathoracic (pulmonary) tuberculosis (TB). Participants are recruited consecutively from children routinely presenting to 2 regional hospitals requiring routine investigation as suspected TB cases. At enrollment, two respiratory samples (any of gastric aspirate [children unable to expectorate], expectorated sputum [older children], induced sputum) from children with suspected intrathoracic TB will be analyzed by smear, culture and GeneXpert Ultra. Minimally invasive samples (blood, urine and stool) will be collected for biomarker work and for storage for future use. In addition, respiratory pathogens and the respiratory microbiome will be tested on nasopharyngeal aspirates collected at baseline and follow-up. Lung function is measured using the novel non-invasive Whistler technique at baseline and at follow- up over 6 months, to track changes in lung function and evaluate functional outcomes. All children undergo clinical and radiological follow-up. The sample size of 300 children with suspected TB will be complemented by 50 healthy sibling controls for the respiratory microbiome and lung function and lung health evaluation (total study population n=350). This study has the aim to investigate the effect of TB, TB/ HIV co-infection and other common respiratory pathogens on lung function in young children. It will investigate the effect of respiratory diseases like TB and respiratory viruses on lung function in young children. In addition it will investigate the changes in lung function measurements over time in these children. The study was approved by the local health research ethics committee from Stellenbosch University and started 23-November-2017. At the end of June 2019; 201 children were enrolled, of which 75 cases, 89 ill controls, healthy sibling controls, and 4 children withdrew. Of the cases 34/75 (45%) were microbiologically confirmed TB. Nasopharyngeal aspirates for viruses and the respiratory microbiome was collected in 195/201 children. Whistler lung function was successful in 83/201 children, with repeat measurements in 25 children. In addition, a total of 107 Spirometry measurements were done (children >4 years of age), with 35 repeat measurements. The impact of this research project will be to help better understand the effect of TB and other pathogens in children living in a resource-limited setting. There is an increasing call for more research into the long-term Reference: 99726 TB- Lung FACT TMA 2015 CDF – 1012 Date submitted: 30-Augustus-2019 Page 9 of 45 Generic Periodic Reporting Template v1 consequences of TB lung disease. The aims of this study are very timous and will allow us to built a cohort of children that can be followed up long-term to investigate effects of TB disease on long-term lung health. The knowledge gained would enable interventions to be implemented to potentially limit disabling chronic lung disease in children and adults, especially COPD. A sound evidence base for the utility of lung function assessment in the study population may also considerably impact on routine clinical care through more objective and feasible assessment of lung function in young children. The principal investigator (Dr Marieke vd Zalm) has has co-organized the first international post TB symposium in 22-23 July 2019, in Stellenbosch. https://blogs.sun.ac.za/dttc/about-us/our-funders-and-research-partners/
Host Organisation
| Department | Institution | Country |
|---|---|---|
| Paediatrics and Child Health | Stellenbosch University (SU) | South Africa |
Sites
Results & Outcomes
Current Organisation
Stellenbosch University, Desmond Tutu TB Centre
Current Job Title
Paediatrician and Clinical researcher
Biography
Publications
Background People who survive tuberculosis face clinical and societal consequences after recovery, including increased risks of recurrent tuberculosis, premature death, reduced lung function, and ongoing stigma. To describe the size of this issue, we aimed to estimate the number of individuals who developed first-episode tuberculosis between 1980 and 2019, the number who survived to 2020, and the number who have been treated within the past 5 years or 2 years.
Methods In this modelling study, we estimated the number of people who survived treated tuberculosis using country-level WHO data on tuberculosis case notifications, excluding those who died during treatment. We estimated the number of individuals surviving untreated tuberculosis using the difference between WHO country-level incidence estimates and notifications, applying published age-stratified and HIV-stratified case fatality ratios. To estimate survival with time, post-tuberculosis life tables were developed for each country-year by use of UN World Population Prospects 2019 mortality rates and published post-tuberculosis mortality hazard ratios.
Findings Between 1980 and 2019, we estimate that 363 million people (95% uncertainty interval [UI] 287 million–438 million) developed tuberculosis, of whom 172 million (169 million–174 million) were treated. Individuals who developed tuberculosis between 1980 and 2019 had lived 3480 million life-years (95% UI 3040 million–3920 million) after tuberculosis by 2020, with survivors younger than 15 years at the time of tuberculosis development contributing 12% (95% UI 7–17) of these life-years. We estimate that 155 million tuberculosis survivors (95% UI 138 million–171 million) were alive in 2020, the largest proportion (47% [37–57]) of whom were in the WHO South-East Asia region. Of the tuberculosis survivors who were alive in 2020, we estimate that 18% (95% UI 16–20) were treated in the past 5 years and 8% (7–9) were treated in the past 2 years.
Interpretation The number of tuberculosis survivors alive in 2020 is more than ten times the estimated annual tuberculosis incidence. Interventions to alleviate respiratory morbidity, screen for and prevent recurrent tuberculosis, and reduce stigma should be immediately prioritised for recently treated tuberculosis survivors.
Background
Limitations in the sensitivity and accessibility of diagnostic tools for childhood tuberculosis contribute to the substantial gap between estimated cases and cases notified to national tuberculosis programs. Thus, tools to make accurate and rapid clinical diagnoses are necessary to initiate more children on antituberculosis treatment.Methods
We analyzed data from a prospective cohort of children <13 years being routinely evaluated for pulmonary tuberculosis in Cape Town, South Africa from March 2012 to November 2017. We developed a regression model to describe the contributions of baseline clinical evaluation to the diagnosis of tuberculosis using standardized, retrospective case definitions. We included results from baseline chest radiography and Xpert MTB/RIF to the model to develop an algorithm with at least 90% sensitivity in predicting tuberculosis.Results
Data from 478 children being evaluated for pulmonary tuberculosis were analyzed (median age: 16.2 months, interquartile range: 9.8-30.9); 242 (50.6%) were retrospectively classified with tuberculosis, of which 104 (43.0%) were bacteriologically-confirmed. The area under the receiver operating characteristic curve for the final model was 0.87. Clinical evidence identified 71.4% of all tuberculosis cases in this cohort, and inclusion of baseline chest radiography results increased the proportion to 89.3%. The algorithm was 90.1% sensitive and 52.1% specific, and maintained a sensitivity of above 90% among children <2 years or with low weight-for-age.Conclusions
Clinical evidence alone was sufficient to make most clinical antituberculosis treatment decisions. The use of evidence-based algorithms may improve decentralized, rapid treatment-initiation, reducing the global burden of childhood mortality.
BACKGROUND:
There is a lack of holistic health-related quality of life (HRQoL) measures for young children with respiratory disease, especially in low- and middle-income countries (LMICs). We aimed to understand caregivers’ perceptions of the relevance of common HRQoL domains for children with respiratory diseases, including TB.
METHODS:
This study was nested in a prospective observational cohort of children presenting with respiratory symptoms presumptive of pulmonary TB. We conducted 10 semi-structured interviews to explore caregivers’ perceptions of the five commonly measured HRQoL domains: physical health, social support, emotional and psychological wellbeing, and schooling. We used case descriptive analysis and thematic coding.
RESULTS:
Caregivers considered all five domains to be relevant. The socio-economic context framed their responses, with QoL requiring sufficient basic resources for children. HRQoL experiences varied according to the severity of the child’s symptoms, but not between TB and non-TB illnesses. Manifestations in the psychological domain were difficult to distinguish from the emotional domain. Social support included broad support for family members, indirectly benefiting the children. Caregivers were concerned about their children’s early developmental milestones and future schooling.
CONCLUSION:
This exploratory study shows that HRQoL domains are relevant but require adaptation to be applicable for young children affected by respiratory illnesses living in LMICs.
Introduction: The chest radiograph (CR) remains a key tool in the diagnosis of pediatric tuberculosis (TB). In children with presumptive intrathoracic TB, we aimed to identify CR features that had high specificity for, and were strongly associated with, bacteriologically confirmed TB.
Methods: We analyzed CR data from children with presumptive intrathoracic TB prospectively enrolled in a cohort study in a high-TB burden setting and who were classified using standard clinical case definitions as "confirmed," "unconfirmed," or "unlikely" TB. We report the CR features and inter-reader agreement between expert readers who interpreted the CRs. We calculated the sensitivity and specificity of the CR features with at least moderate inter-reader agreement and analyzed the relationship between these CR features and the classification of TB in a multivariable regression model.
Results: Of features with at least moderate inter-reader agreement, enlargement of perihilar and/or paratracheal lymph nodes, bronchial deviation/compression, cavities, expansile pneumonia, and pleural effusion had a specificity of > 90% for confirmed TB, compared with unlikely TB. Enlargement of perihilar (adjusted odds ratio [aOR]: 6.6; 95% confidence interval [CI], 3.80-11.72) and/or paratracheal lymph nodes (aOR: 5.14; 95% CI, 2.25-12.58), bronchial deviation/compression (aOR: 6.22; 95% CI, 2.70-15.69), pleural effusion (aOR: 2.27; 95% CI, 1.04-4.78), and cavities (aOR: 7.45; 95% CI, 3.38-17.45) were associated with confirmed TB in the multivariate regression model, whereas alveolar opacification (aOR: 1.16; 95% CI, .76-1.77) and expansile pneumonia (aOR: 4.16; 95% CI, .93-22.34) were not.
Conclusions: In children investigated for intrathoracic TB enlargement of perihilar or paratracheal lymph nodes, bronchial compression/deviation, pleural effusion, or cavities on CR strongly support the diagnosis.
Introduction
Bronchoscopy can be a useful tool in children with pulmonary tuberculosis (PTB) with severe disease potentially requiring intervention or in the face of diagnostic dilemmas. The aim of this study was to determine the value of Xpert MTB/RIF assay (Xpert) on bronchoalveolar lavage (BAL) samples in children with complicated PTB.Methods
Retrospective analysis of children with clinically diagnosed PTB, who underwent routine bronchoscopy over a five year period at a large referral hospital. BAL and other respiratory samples were tested by microscopy, culture and Xpert. We explored whether clinical, radiographic and bronchoscopy findings, and duration of antituberculosis treatment were associated with bacteriological confirmation.Results
112/146 (76.7%) children (median age 16 months) were on antituberculosis treatment for a median of 10 days at the time of bronchoscopy. Overall, bacteriological confirmation was achieved in 115 (78.7%), with 101 (69.2%) detected on BAL. Of those bacteriologically confirmed on BAL, 61.4% were positive by both Xpert and culture, 34.7% only by Xpert and 3.9% only by culture. Sensitivity and specificity of Xpert compared to culture on BAL samples for children not on antituberculosis treatment were 94.1% (95% CI 71.3, 99.8) and 68.7% (95% CI 41.3, 89.0), respectively.Conclusions
In children undergoing bronchoscopy for complicated PTB, Xpert testing of BAL had a high diagnostic yield in children already on antituberculosis treatment. Bronchoscopy should be considered if non-invasive respiratory specimens fail to confirm complicated TB. This article is protected by copyright. All rights reserved.
Introduction: A considerable burden of the tuberculosis (TB) epidemic is found in adolescents. The reasons for increased susceptibility to TB infection and higher incidence of TB disease in adolescence, compared with the 5-10 years old age group, are incompletely understood. Despite the pressing clinical and public health need to better understand and address adolescent TB, research in this field remains limited.
Methods and analysis: Teen TB is an ongoing prospective observational cohort study that aims to better understand the biology, morbidity and social context of adolescent TB. The study plans to recruit 50 adolescents (10-19 years old) with newly diagnosed microbiologically confirmed pulmonary TB disease and 50 TB-exposed controls without evidence of TB disease in Cape Town, South Africa, which is highly endemic for TB. At baseline, cases and controls will undergo a detailed clinical evaluation, chest imaging, respiratory function assessments and blood collection for viral coinfections, inflammatory cytokines and pubertal hormone testing. At 2 weeks, 2 months and 12 months, TB disease cases will undergo further chest imaging and additional lung function testing to explore the patterns of respiratory abnormalities. At week 2, cases will complete a multicomponent quantitative questionnaire about psychological and social impacts on their experiences and longitudinal, in-depth qualitative data will be collected from a nested subsample of 20 cases and their families.
Ethics and dissemination: The study protocol has received ethical approval from the Stellenbosch University Health Research Ethics Committee (N19/10/148). The study findings will be disseminated through peer-reviewed publications, academic conferences and formal presentations to health professionals. Results will also be made available to participants and caregivers.
The effects of SARS-CoV-2 variants on disease phenotype and severity of multisystem inflammatory syndrome in children (MIS-C) are unknown. We compared the clinical phenotype of MIS-C in 129 South African children across four distinct (Ancestral type, Beta, Delta, and Omicron) variant-driven waves and found that MIS-C remains a severe disease with a stable clinical presentation, regardless of variant.
Background: Identification of SARS-CoV-2 infected individuals is imperative to prevent hospital transmission, but symptom-based screening may fail to identify asymptomatic/mildly symptomatic infectious children and their caregivers.
Methods: A COVID-19 period prevalence study was conducted between 13 and 26 August 2020 at Tygerberg Hospital, testing all children and their accompanying asymptomatic caregivers after initial symptom screening. One nasopharyngeal swab was submitted for SARS-CoV-2 using real-time reverse-transcription polymerase chain reaction (rRT-PCR). An additional Respiratory Viral 16-multiplex rRT-PCR test was simultaneously done in children presenting with symptoms compatible with possible SARS-CoV-2 infection.
Results: SARS-Co-V 2 RT-PCR tests from 196 children and 116 caregivers were included in the analysis. The SARS-CoV-2 period prevalence in children was 5.6% (11/196) versus 15.5% (18/116) in asymptomatic caregivers (p<0.01). Presenting symptoms did not correlate with SARS-CoV-2 test positivity; children without typical symptoms of SARS-CoV-2 were more likely to be positive than those with typical symptoms (10.2% [10/99] vs 1% [1/97]; p<0.01). Children with typical symptoms (97/196; 49.5%) mainly presented with acute respiratory (68/97; 70.1%), fever (17/97; 17.5%), or gastro-intestinal complaints (12/97; 12.4%); Human Rhinovirus (23/81; 28.4%) and Respiratory Syncytial Virus (18/81; 22.2%) were frequently identified in this group. Children-caregiver pairs' SARS-CoV-2 tests were discordant in 83.3%; 15/18 infected caregivers' children tested negative. Symptom-based COVID-19 screening alone would have missed 90% of the positive children and 100% of asymptomatic but positive caregivers.
Conclusion: Given the poor correlation between SARS-CoV-2 symptoms and RT-PCR test positivity, universal testing of children and their accompanying caregivers should be considered for emergency and inpatient paediatric admissions during high COVID-19 community transmission periods. Universal PPE and optimising ventilation is likely the most effective way to control transmission of respiratory viral infections, including SARS-CoV-2, where universal testing is not feasible. In these settings, repeated point prevalence studies may be useful to inform local testing and cohorting strategies.
Background
People who survive tuberculosis face clinical and societal consequences after recovery, including increased risks of recurrent tuberculosis, premature death, reduced lung function, and ongoing stigma. To describe the size of this issue, we aimed to estimate the number of individuals who developed first-episode tuberculosis between 1980 and 2019, the number who survived to 2020, and the number who have been treated within the past 5 years or 2 years.Methods
In this modelling study, we estimated the number of people who survived treated tuberculosis using country-level WHO data on tuberculosis case notifications, excluding those who died during treatment. We estimated the number of individuals surviving untreated tuberculosis using the difference between WHO country-level incidence estimates and notifications, applying published age-stratified and HIV-stratified case fatality ratios. To estimate survival with time, post-tuberculosis life tables were developed for each country-year by use of UN World Population Prospects 2019 mortality rates and published post-tuberculosis mortality hazard ratios.Findings
Between 1980 and 2019, we estimate that 363 million people (95% uncertainty interval [UI] 287 million-438 million) developed tuberculosis, of whom 172 million (169 million-174 million) were treated. Individuals who developed tuberculosis between 1980 and 2019 had lived 3480 million life-years (95% UI 3040 million-3920 million) after tuberculosis by 2020, with survivors younger than 15 years at the time of tuberculosis development contributing 12% (95% UI 7-17) of these life-years. We estimate that 155 million tuberculosis survivors (95% UI 138 million-171 million) were alive in 2020, the largest proportion (47% [37-57]) of whom were in the WHO South-East Asia region. Of the tuberculosis survivors who were alive in 2020, we estimate that 18% (95% UI 16-20) were treated in the past 5 years and 8% (7-9) were treated in the past 2 years.Interpretation
The number of tuberculosis survivors alive in 2020 is more than ten times the estimated annual tuberculosis incidence. Interventions to alleviate respiratory morbidity, screen for and prevent recurrent tuberculosis, and reduce stigma should be immediately prioritised for recently treated tuberculosis survivors.Funding
UK Medical Research Council, the UK Department for International Development, the National Institute for Health Research, and the European and Developing Countries Clinical Trials Partnership.
Methods: In an observational cohort study, children < 13 years were routinely investigated for suspected PTB in Cape Town, South Africa between December 2015 and September 2017 and followed up for 24 weeks. Nasopharyngeal aspirates (NPAs) were tested for respiratory viruses using multiplex PCR at enrolment, week 4 and 8.
Results: Seventy-three children were enrolled [median age 22.0 months; (interquartile range 10.0-48.0); 56.2% male and 17.8% HIV-infected. Anti-tuberculosis treatment was initiated in 54.8%; of these 50.0% had bacteriologically confirmed TB. At enrolment, ≥1 virus were detected in 95.9% (70/73) children; most commonly human rhinovirus (HRV) (74.0%). HRV was more frequently detected in TB cases (85%) compared to ill controls (60.6%) (p = 0.02). Multiple viruses were detected in 71.2% of all children; 80% of TB cases and 60.6% of ill controls (p = 0.07). At follow-up, ≥1 respiratory virus was detected in 92.2% (47/51) at week 4, and 94.2% (49/52) at week 8.
Conclusions: We found a high prevalence of viral respiratory co-infections in children investigated for PTB, irrespective of final PTB diagnosis, which remained high during follow up. Future work should include investigating the whole respiratory ecosystem in combination with pathogen- specific immune responses.